Effective treatments for androgen-independent prostate cancer (AIPCa) are lacking. To address this, emerging therapeutics such as proteasome inhibitors are currently undergoing clinical trials. Inositol hexakisphosphate (IP6) is an orally non-toxic phytochemical that exhibits antitumour activity against several types of cancer including PCa. We have previously shown that treatment of PC3 cells with IP6 induces the transcription of a subset of nuclear factor-kB (NF-kB)-responsive and pro-apoptotic BCL-2 family genes. In this study, we report that although NF-kB subunits p50/p65 translocate to the nucleus of PC3 cells in response to IP6, inhibition of NF-kBmediated transcription using non-degradable inhibitor of kB (IkB)-a does not modulate IP6 sensitivity. Treatment with IP6 also leads to increased protein levels of PUMA, BIK/NBK and NOXA between 4 and 8 h of treatment and decreased levels of MCL-1 and BCL-2 after 24 h. Although blocking transcription using actinomycin D does not modulate PC3 cell sensitivity to IP6, inhibition of protein translation using cycloheximide has a significant protective effect. In contrast, blocking proteasome-mediated protein degradation using MG-132 significantly enhances the ability of IP6 to reduce cellular metabolic activity in both PC3 and DU145 AIPCa cell lines. This effect of combined treatment on mitochondrial depolarisation is particularly striking and is also reproduced by another proteasome inhibitor (ALLN). The enhanced effect of combined MG132/IP6 treatment is almost completely inhibited by cycloheximide and correlates with changes in BCL-2 family protein levels. Altogether these results suggest a role for BCL-2 family proteins in mediating the combined effect of IP6 and proteasome inhibitors and warrant further pre-clinical studies for the treatment of AIPCa.
Objectives: In the present study, we investigated whether the pH of IP6 could influence its anti-tumoral activity in vitro. Methods: PC-3 cells were exposed to IP6 at pH 5, pH 7, and pH 12 and we evaluated the metabolic activity (WST-1 assay), cell proliferation (cell count), cell cycle distribution (FACS), and mitochondrial depolarization (JC-1 staining) in vitro. Results: Our results demonstrated that IP6 at pH 5 and pH 12 were more potent at lowering the metabolic activity of PC-3 cells than IP6 at pH 7. Treatment with IP6 at pH 12 also caused the greatest inhibition in cellular proliferation and accumulation of PC-3 cells in sub-G1. Finally, IP6 at pH 12 lead to a reduction in phospho-AKT and phospho-PDK1 and upregulated phospho-ERK. Conclusion: Together, our data strongly suggest that the pH of IP6 effectively modulates its anti-tumoral activity and should be reported in future studies.
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